4, 5-diacyl-3-hydroxy-3-pyrrolin-2-ones



Unitedstates Patent 3,244,725 4,5-DIACYL-3-HYDROXY-3-PYRROLIN-2-ONESWilliam Taub, 43 Ben-Zion St., Rehovoth, Israel, and

Sander Vromen, 5 Vitkin St., Haifa, Israel N 0 Drawing. Filed Sept. 21,1964, Ser. No. 398,042 6 Claims. (Cl. 260-3265) This invention relatesto new organic compounds having useful pharmacodynamic activity. Morespecifically, these 4,S-diacyl-3-hydroxy-3-pyrrolin-2-one derivativeshave anti-phlogistic, antipyretic and anti-inflammatory activity. Thesecompounds also have utility as intermediates for preparing relatedcompounds having like activities.

The compounds of this invention are illustrated by the followingformula:

The three starting materials are condensed by reaction at moderatetemperatures such as from room temperature up to the reflux temperatureof the reaction mixture. An inert organic solvent in which the reactantsare substantially soluble is usually used such as ethanol, methanol orisopropanol. Preferably the substituted glyoxal is reacted with theamine then in turn with the lower alkyl acyl pyruvate. The desiredproduct either crystallizes from the mixture or is isolated by standardprocedures.

The bisacyl-a-keto l-actams of this invention are sufficiently acid toform salts with various organic or inorganic bases. The alkali metalsalts are preferred such as the potassium or sodium salts. Otherpharmaceutically acceptable salts with nontoxic cations may be preparedby methods known to those skilled in the art. Also, ester or etherderivatives at this grouping may be prepared as desired.

Also variations of the compounds represented by Formula I may be made asknown to those skilled in the medicinal art, for example, usingthiophene or furan for R or R substituting inert substituents on thearyl rings such as halo, lower alkoxy, trilluoromethyl, etc. Suchobvious modifications are considered a part of this invention.

The terms lower alkyl or lower alkoxy are used to define terms of acarbon content of 18 preferably l-2.

The following examples are designed to teach the preparation ofrepresentative compounds of this invention.

EXAMPLE 1 Glyoxal The methyl ketone (0.5 mole) is added dropwise to 0.5mole of selenium dioxide suspended in 300 ml. of diox-ane containing 1%of water While stirring and heating at reflux for from 2-6 hours. Theclear solution is filtered hot and the residue from the filtratefractionally distilled.

Acylpyruvate esters Sodium metal (1 2.5 g.) is reacted with 280 ml. ofabsolute ethanol. The mixture is cooled to about 0 C. whilediethyloxalate (0.5 mole) is added dropwise. The desired methyl ketone(R COCH is then added dropwise. The condensation product is removed byfiltration and isolated as either the sodium salt or prefer-ably thefree ester obtained by neutralizing an aqueous solution of the salt andextraction with ether.

EXAMPLE 2 Diacylpyrrolinones A mixture of 5 ml. of absolute ethanol and0.001 mole of amine (R NH is stirred while 0.001 mole of the glyoxal isadded (R COCHO) at room temperature. Then 0.001 mole of the lower alkylacylpyruvate (R COCH COCO R) in 25 ml. of absolute ethanol is addeddropwise. The mixture is heated at reflux for 10-60 minutes. Thestirring is continued until the mixture cools to room temperature. Thewhole reaction mixture is left in a cold place to crystallize thedesired pyrrolinone. If no crystallization takes place, the solvent isremoved and the residue purified by trituration with various solvents(such as carbon tetrachloride, chloroform, etc.) or by distillationunder high vacuum.

Using this method the following compounds are prepared.

No. R1 R2 R M.P LR. (cm.-

a-Naphthyl Cyelopropyl -d0 t-Butyl Cyclopentyl- Cyclopropyl Methoxy 0 do6 Cyelohexyl- 0 -do n-Dodecyl. Oil 1,690, 1,760 n-Hexyl Oil 1,720, 1,760Cycllohexyl- 129-131 o 1,720, 1,770 1,740, 1,780 1,710, 1,740 1,680,1,740

Benzyl 21- Allyl 3 An aliquot of a compound described above in methanolis treated with one equivalent of sodium or potassium mcthylate inmethanol. The mixture is then evaporated to dryness to give the desiredalkali metal salt.

What is claimed is: 1. The compound of the formula:

OH it Rz-C- in which R and R are members selected from the groupconsisting of alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms,phenyl, naphthyl, benzyl, :benzyloxy and, except for R alkoxy of 1-2carbon atoms and R is a member selected from the group consisting ofalkyl of 1-12 carbon atoms, cycloalkyl of 3-6 carbon atoms, naphthyl andbenzyl. 7

2. The compound of the formula:

3. The compound of the formula:

DEW-on 4. The compound of the formula:

( liHo 5. The compound of the formula:

ll v y 56115 6. The method of preparing compounds having the formula:

No references cited.

HENRY R. JILES, Primary Examiner.

I. A. NARCAVAGE, Assistant Examiner.

1. THE COMPOUND OF THE FORMULA: